DE2256755A1 - Amidines preparation - by reacting silylated amides or lactams with ammonia or amines - Google Patents

Abstract

Optionally substituted amidines are prepared by (a) silylating an amide or lactam (pref. with hexamethyldisilazane in the presence of trimethylchlorosilane or an ammonium salt) and (b) reacting the resulting silyl derivative with ammonia or a primary or secondary amine or a salt thereof in the presence of a tertiary base and of a Lewis acid as catalyst. This gives amidines which are pharmaceuticals useful as antidiabetics, antiprotozoals, antibacterials, cytostatics, local anaesthetics and virustatics. The new (and claimed) compound 2-(DELTA 2-imidazolin-2-yl)-5-nitro-thiazole has antifungal and antibacterial activity.

Description

Process for the preparation of amidines and new amidines The invention relates to a process for the preparation of unsubstituted and substituted amidines and new amidines.

As a method for the production of amidines so far are essentially the production from nitriles directly by reaction with amines or from Nitrilen..over the imidocarboxylic acid ester by reaction with appropriate alcohols and then applied with amines. The disadvantage of the.

first method is that either very reactive nitriles or drastic reaction conditions are required. The disadvantage of the second The process consists in the fact that it is a costly two-step process.

It has now been found that amidines are easy and in good yields from amides and lactams by silylation and subsequent reaction with ammonia or have amines produced.

The invention is therefore a process for the production of unsubstituted and substituted amidines, characterized in that that one amides Qof the lactams silyliartand the silyl derivatives obtained with ammonia or a primary or secondary amine or a salt of the amine in the presence of one tertiary base in the presence of a Lewis acid as a catalyst.

As amides, there are aliphatic and aromatic amides1 and there are others May contain substituents in question. The lactams are unsubstituted and substituted lactams are possible.

Preferred substituents are amino, substituted amino, such as phenethylamino, alkyl, substituted alkyl, such as benzyl and trimethoxybenzyl, Aryl, such as phenyl, substituted aryl, such as p-chlorophenyl, and alkoxy groups as well Halogen atoms in question.

Alkyl and alkoxy groups should preferably be groups with 1 - 8 carbon atoms are understood.

The amine components are primary and secondary aliphatic and cyclic amines.

Suitable substitutes for the amine component are preferably Alkyl, aralkyl, aryl or heterocyclic groups, which have further substituents can wear, and groups or the substituents form together with the N atom forms a heterocyclic ring, which contains further heteroatoms such as O-, N- or may contain S atoms and substituted by one or more substituents can be.

The silylation is preferably carried out with hexamethyldisilazane in the presence of trimethylchlorosilane or an ammonium salt, optionally with the addition of a tertiary base such as pyridine, made at the boiling point.

Primary and secondary amino groups present in the molecule become simultaneously silylated. These N-silyl groups become in the following reaction with ammonia or an amine is split off again in the presence of a Lewis acid.

It is not necessary for the reaction according to the invention to use the silyl compounds to isolate. The trimethylsilyl compounds formed in situ can be in the reaction solution be reacted directly with ammonia or an amine to give the corresponding amidines.

The type of implementation depends on the amine component and the catalyst @. The treatment of the silyl compound with primary or secondary amines takes place Preferably at'O0 to iSo0 C. When using primary and secondary salts Amine is worked in the presence of a tertiary 'amine', the amine salt can also serve as a catalyst.

As tertiary amines, for example: trimethylamine, Triethylamine, ethyldiisopropylamine, pyridine, quinoline, etc.

Examples of primary amines are :, methylamine, ethylamine, Propylamine, butylamine, aniline, p-anisidine, benzylamine, homoveratrylamine, tryptamine, N, N-dimethylethylenediamine, etc.

As secondary amines are preferably in frgge: dimethylamine, diethylamine, Pyrrolidine, piperidine, morphine, hexamethyleneimine, N-methyl-piperazine, etc.

Since the primary amines can react with the silylating agent, should include the addition of the primary amine after the silyl compound has been formed and removed of the silylation reagent take place In contrast to the primary amines react the secondary amines only sluggishly with the silylating agent. Silylating agents and secondary amine can therefore optionally be used at the same time.

The reaction with ammonia is carried out under increased NH3 pressure of about 20 - 50 atU. The reaction is after 20 to 80 hours at 0 to 1800 C completed. In the case of silylation with hexamethyldisilazane, in which ammonia is used anyway becomes free, can Silylation and reaction with ammonia in one Stage.

The excess amine component is particularly suitable as a solvent for the reaction. but there are also inert solvents, such as toluene, xylene, Chlorobenzene, anisole, dioxane, glyme, tetrachloroethane or for the less soluble Silyl compounds are preferably dimethylformamide.

Lewis acids, in particular metal salts, and Salts of amines into consideration. The metal salts are optionally used with excess Amine component used in the reaction.

The catalysts are obtained in amounts from 0.001 mol to 5 mol on the amide or the lactam, but preferably in amounts of 0.05 to 1 mol, ion the reaction used.

Mercury (II) chloride and mercury (II) acetate have proven to be the most effective and tin-IV-chloride as well as zinc-II-chloride, titanium-IV-chloride and boron trifuluoride etherate, which are used in nation with excess amine, and salts of amines, such as for example ammonium sulfate, ß-phenethylamine hydrochloride, homoveratrylamine hydrochloride etc.

The course of the reaction is surprising because it occurs during the silylation one Amides or lactams mainly formed the N-silyl and not the 0-silyl compound will. Only because the addition of the catalyst makes the equilibrium strong Is shifted in favor of the 0-silyl compound, the course of the reaction is closed explain.

The amidines which can be prepared by the process according to the invention are valuable -Arz'neimittel as antidiabetic, as antiprotozoal, as antibacterial Find active ingredients as cytostatics, local anesthetics and virus statics (see A. Kreutzberger in Progress in Drug Research, Vol. II (1968), page 356 - 445).

The invention furthermore relates to new ones according to the invention Process preparable compounds, such as, for example, 2 - (# 2-2-Imidazolinyl) -5-nitro-thiazole, which has antifungal and antibacterial properties.

The following examples are intended to explain the process according to the invention in more detail explain without limiting it.

For example 1 (phenethyl) - (4.5.6.7-tetrahydro-3H-azepin-2-yl) amine 3.4 g (30 mmol) of caprolactam are obtained by heating for one hour. 145 ° C in 100 ml of hexamethyldisilazane and 0.5 ml of trimethylchlorosilane dissolved, the reagents in 125 ° C distilled off and the residue with 31.6 ml (250 mmol) ß-phenethylamine, 0.8 g (3 mmol) of HgCl2 and 3 ml of hexamethyldisilazane for 15 hours at 150 ° C under an argon atmosphere touched. After standing at room temperature, 300 ml of chloroform are added and extracted with 75 ml of ln NaOH. The organic phase is dried over Na2SO4 and the solvent removed in vacuo. 6.55 g (91% of theory) of oily remain (Phenethyl) - (4.5.6.

tetrahydro-3H-azepin-2-yl) amine.

Example 2 N.N- (3-oxa-pentamethylene) -benzamidine 3.63 g (30 mmol) of benzamide are obtained by heating for 2 hours at 145 ° C. in 100 ml of hexamethyldisilazane and 1 ml of trimethylchlorosilane dissolved, the reagents distilled off at 1250 C and the residue with 7.83 ml (90 mmol) of morpholine and 0.81 g (3 mmol) of HgC12 for 4 hours stirred at 1200 C under an argon atmosphere. After cooling, it is mixed with 150 ml of methanol Reflux for 30 minutes boiled and the solvent removed. The residue is then dissolved in 100 ml of H20 and repeatedly with chloroform extracted. The organic phase is dried over Na2SO4 and the solvent peeled off in vacuo.

4.28 g (75% of theory) of oily N.N- (3-oxapentamethylene) benzamidine remain.

Example 3 (4-anisyl) - (4.5.6.7-tetrahydro-3H-azepin-2-yl) -amine.

3.4 g (30 mmol) of caprolactam are heated to 1450 for 2 hours C dissolved in 100 ml of hexamethyldisilazane and 1 ml of trimethylsilyl chloride, the reagents distilled off at 125 ° C. and the residue with 4.93 g (40 mmol) of p-anisidine and 0.35 ml (3 mmol) of SnCl4 was stirred for 5 hours at 1200 C under an argon atmosphere. After adding of 150 ml of methanol is refluxed for 1 hour, the reaction mixture with Activated charcoal is clarified and the solvent is distilled off in vacuo. It remains 4.98 g (76% of theory) oily (4-anisyl) - (4.5.6.7-tetrahydro-3H-azepin-2-yl) amine.

Example, 4 Benzamidine 3.634 g (30 mmol) of benzamide are in the autoclave with 20 ml of hexamethyldisilazane, 20 ml of ethylene glycol dimethyl ether, 5 ml of ethylene glycol monomethyl ether and 0.814 g (3 mmol) of HgC12 were added. Then there is enough ammonia within 30 minutes initiated that the pressure reaches 35 atm and then the autoclave 45 hours heated to 1550 C internal temperature. After cooling, the residue becomes 30 minutes boiled under reflux with 100 ml of methanol, the reaction solution clarified with activated charcoal and the solvent removed in vacuo. It remains after cleaning by sublimation ?, 59 g (72% of theory) benzamidine; Melting point: 71 - 720 C.

Example 5 4- (5-Oxo- # 1-2H-pyrrolinyl) -morpholine 2.48g (25mmol) succinimide 100 ml of hexamethyldisilazane and 1 ml of trimethylsilyl chloride are obtained by boiling for 3 hours dissolved, the reagents are 'distilled off and the residue with 6.4 ml (75 mmol) Morpholine and 0.68 g (2.5 mmol) of HgC12 for 4 hours at 1200 C under an argon atmosphere touched. After cooling, it is refluxed with 100 ml of methanol for 1 hour, the reaction solution is clarified with activated charcoal and the solvent is distilled off in vacuo. After recrystallization from benzene, 3.11 g (74 ffi of theory) of 4- (5-oxo-h) remain -2H-pyrrolinyl) -morpholine with a melting point of 113 - 1150 C.

Example 6 2- (2-2-Imidazolinyl) -5-nitro-thiazole hydrochloride.

2.6 g (15 mmol) of 5-nitro-2-acetamido-thiazole are through 7 hours Heat to 1450 ° C. in 50 ml of hexamethyldisilazane and 0.5 ml of trimethylsilyl chloride dissolved, the reagents were distilled off and the residue with 4.16 g (15 mmol) of HgC12 and 6 ml of dimethylformamide (absolute) are added. Then within an hour the Solution of 1 ml (15 mmol) of ethylenediamine in 10 ml of dimethylformamide (absolute) was added and the reaction mixture was stirred for a further 16 hours at room temperature. Afterward is with 50 ml of methanol (absolute) offset, H2S introduced for 15 minutes, the reaction solution is clarified with activated charcoal and the solvent is removed in vacuo. After recrystallization from methanol, 2.68 g (55% of theory) of 2 - (# 2-2-imidazolinyl) -5-nitro-thiazole hydrochloride remain.

Claims (2)

Claims 1) Process for the preparation of unsubstituted and substituted Amidines, characterized in that amides or lactams are silylated and the resulting Silyl derivatives with ammonia or a primary or secondary amine or a salt of the amine in the presence of a tertiary base in the presence of a Lewis acid as Catalyst converts. 2) 2 - (# 2-2-Imidazolinyl) -5-nitro-thiazole.